Scientists at Washington University School of Medicine (WUSM) in St. Louis have spent some years investigating the links between circadian rhythm and Alzheimers, and have recently been making some real inroads. Following a 2018 study demonstrating how disrupted sleep can accelerate the buildup of toxic plaques associated with the disease, the team has now identified a protein implicated in the progression of the disease that appears highly regulated by the circadian rhythm, helping them join the dots and providing a potential new therapeutic target.

In their previous research, the WUSM team set out to explore how disruptions to our natural sleep cycles, or circadian rhythm, may accelerate the accumulation of amyloid plaques in the brain, which are strongly linked to Alzheimers disease. Through studies on humans and in mice, the team was able to show a strong correlation between the two, and now through follow up work, the team has identified a brain protein that appears to play a role in this relationship.

The brain protein in question is called YKL-40 and for years has served as a biomarker for Alzheimers, as high levels of it have been found in the cerebrospinal fluid of those suffering from the disease and these levels rise as the disease progresses. The researchers were screening for genes that are regulated by the circadian rhythm, and were intrigued to see the gene for this brain protein pop up.

The gene for YKL-40 came up as highly regulated by clock genes, says Erik Musiek, senior author. That was really interesting because it is a well-known biomarker for Alzheimers.

From there, the team investigated this connection between YKL-40 and Alzheimers, which is characterized by chronic inflammation, by exploring how much of the protein is made under inflammatory conditions both with and without a key circadian gene. Indeed, this demonstrated that the circadian rhythm controls how much YKL-40 is produced.

If you have inflammation in the morning, you might get lots of YKL-40; if you get inflammation in the evening, when the clocks in a different phase, you might get less YKL-40, Musiek says.

Next up, the team worked with mice prone to developing amyloid plaques, and genetically modified one group of them to be lacking the gene for YKL-40. As the mice reached old age, the team analyzed their brains and found that those without the YKL-40 protein exhibited around half the amyloid plaques of the control group.

Digging deeper into the reasons why, the team found that the mice lacking the YKL-40 gene featured more microglia, which are immune cells that surround amyloid plaques and prevent them from spreading. Essentially, this meant that those mice had more hungry immune cells prepared to gobble up the amyloid.

This YKL-40 protein probably serves as a modulator of the level of microglial activation in the brain, Musiek says. When you get rid of the protein, it appears the microglia are more activated to eat up the amyloid. Its a subtle thing, a tweak in the system, but it seems to be enough to substantially reduce the total amyloid burden.

The team also examined this idea in human subjects, drawing on genetic data on 778 subjects from aging and dementia studies and finding only a quarter of them featured a genetic variant that lowers levels of YKL-40, and that cognitive function declined 16 percent more slowly in that group.

If your circadian clock is not quite right for years and years you routinely suffer from disrupted sleep at night and napping during the day the cumulative effect of chronic dysregulation could influence inflammatory pathways such that you accumulate more amyloid plaques, says Musiek. We hope that a better understanding of how the circadian clock affects YKL-40 could lead to a new strategy for reducing amyloid in the brain.

The research was published in the journal Science Translational Medicine.

Source: Washington University School of Medicine in St. Louis

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Biomarker of Alzheimer's found to be regulated by sleep cycles - New Atlas